Indoline-2-carboxylic acids have heretofore been prepared by first forming the corresponding indole-2-carboxylic acid and then reducing the 2,3-double bond. The chief drawback in such preparations has been the lack of a satisfactory process for reducing the 2,3-double bond.
One of the methods of obtaining the indole-2-carboxylic acid to be reduced has been via the Reissert synthesis wherein o-nitrophenylpyruvic acid (III above where X is hydrogen) is reductively cyclized directly to the indoline-2-carboxylic acid using zinc and acetic acid or ferrous sulfate and ammonium hydroxide. See Weissberger, ed., The Chemistry of Heterocyclic Compounds, Vol. 25, part 1, pp. 396-399 (Wiley Interscience, New York, 1972).
Three methods are reported for reducing indole-2-carboxylic acid to indoline-2-carboxylic acid. Hudson and Robertson, Australian Journal of Chemistry, 20, 1935-41 (1967), first converted the acid to the amide and reduced the 2,3-double bond of the amide using phosphonium iodide/hydriodic acid. They then converted the resulting indoline-2-carboxamide to the desired indoline-2-carboxylic acid by hydrolysis. Y. Omote et al., Nippon Kagaku Zasshi, 87, 760 (1966), also reported an indirect reduction [See Stanton et al., Journal or Medicinal Chemistry, 26, 1267-77 at 1268 (1983)]. In this method the indole-2-carboxylic acid was first converted to the N-acetyl derivative which was reduced by hydrogenation at atmospheric pressure in the presence of platinum oxide. The resulting N-acetyl-indoline-2-carboxylic acid was then hydrolyzed to remove the acetyl group. Corey et al., Journal of the American Chemical Society, 92, 2476-2488, at 2480 (1970), directly reduced indole-2-carboxylic acid ethyl ester using excess dry hydrogen chloride gas and tin and absolute ethanol in a sealed bomb.
After obtaining indoline-2-carboxylic acid by one of these procedures, a resolution process would then have to be performed in order to obtain the desired chiral indoline-2-carboxylic acid. Here also one of the reported resolutions is indirect in that the indoline-2-carboxylic acid is first converted to its N-acetyl derivative. This derivative is resolved and the resolution product is converted back to the indoline-2-carboxylic acid. See Example 1 of U.S. Pat. No. 4,374,847 to N. Gruenfeld. A direct resolution of indoline-2-carboxylic acid using (+)-.alpha.-methylbenzylamine as a resolving agent is reported in Tetrahedron Letters, Vol. 23, No. 16, pp. 1677-80, at 1678 (April/May, 1982). However, no detail on yields is given in this report.
Applicants' process differs from all prior processes for the preparation of I or II in that either I or II, as desired, may be obtained as a single enantiomer without the concurrent formation of the opposing optical antipode.
The classical resolution process, as described above, which involves the generation of both optical enantiomers followed by separation of the desired from the undesired enantiomer, is less efficient because half of the material generated is lost in the form of the undesired enantiomer. The invention process is more efficient since it decreases the amount of material that is lost in the form of the undesired enantiomer.
The indoline-2-carboxylic acids of Formula I are useful as starting materials for the preparation of N-(3-mercapto-2-alkyl-1-oxopropyl)-indoline-2-carboxylic acids and N-(2-substituted-1-oxoalkyl)-indoline-2-carboxylic acids thereof which have antihypertensive and angiotensin converting enzyme (ACE) inhibitory properties. These antihypertensive agents and ACE inhibitors are disclosed in U.S. Pat. No. 4,303,583, issued on Dec. 1, 1981, to D. H. Kim and R. J. McCaully and in U.S. Pat. No. 4,350,633, issued on Sept. 21, 1982, also to D. H. Kim and R. J. McCaully. The indoline-2-carboxylic acids of structural Formulas I and II are useful as intermediates in further asymmetric syntheses of a variety of .alpha.-amino acids. (E. J. Corey, R. J. McCaully, H. S. Sachdev, J. Am. Chem. Soc., 1970, 92, 2476).